PROJECT SUMMARY This proposal titled ?MicroRNA-based interventions to prevent progression from lung preneoplasia to adenocarcinoma? is responsive to PQ1. Lung cancer is the most common cause of cancer-related mortality worldwide. Despite advances in detection and improvements to standard of care, the overall survival rate for lung cancer patients remains very low (5). This poor survival rate is probably due to the relatively advanced stage of the disease at diagnosis. If lung cancer could be identified and stopped at a preneoplastic stage prior to progression into advanced stage, we could improve the patients' survival. However, little is known about the biomarkers distinguishing preneoplasia from normal tissues and the molecules driving preneoplasia initiation and progression. Recent evidence has shown that intratumor cellular heterogeneity contributes to tumor initiation and progression of cancer, including lung cancer (6). Tumor-initiating cells (TICs) or cancer stem cells are a subpopulation of the bulk of tumor cells that can recapitulate the whole tumor's heterogeneous structures and functionally drive tumorigenesis. Nuclear factor-?B (NF-?B) is the key mediators of the inflammation response and has been recently been implicated as a driver of TICs (7). More recently, it has been found that inflammation can change expression of some microRNAs (miRNAs), including upregulation of oncogenic miR-21 (8). MiRNAs are non-coding RNAs belonging to a novel class of regulatory molecules that control gene expression by binding to complementary sites on multiple target messenger RNA (mRNA) transcripts simultaneously (9). However, the signaling events that link cancer stemness-related miRNAs to preneoplasia initiation and progression in inflammatory microenvironments remain to be charted. We hypothesize that inflammation induced miRNA dysregulation on TICs might drive preneoplasia initiation and progression in KRASmut or epidermal growth factor receptor (EGFRmut) lung adenocarcinoma patients, and that a deeper understanding of this may identify novel targets for miRNA-based therapeutics. In Aim 1, we will characterize a miRNA signature in preneoplasia in lung tissues. In Aim 2, we will investigate roles of miRNA inhibitors or mimics in preventing progression from preneoplasia to neoplasia in lung. At the conclusion of these studies, we will have generated a new tumor organoid model, developed miRNA therapeutics useful in curing preneoplasia and preventing malignant progression, as well as gained innovative information regarding roles of both TICs and the inflammatory niche in preneoplasia initiation and progression.